This presentation includes off-label and/or investigational uses of drugs, including clopidogrel and cangrelor.

Transcription

1 CHAMPION PHOENIX Deepak L. Bhatt, MD, MPH, Gregg W. Stone, MD, Kenneth W. Mahaffey, MD, C. Michael Gibson, MS, MD, Ph. Gabriel Steg, MD, Christian Hamm, MD, Matthew Price, MD, Sergio Leonardi, MD, Dianne Gallup, MS, Meredith Todd, Simona Skerjanec, PharmD, Harvey D. White, DSc, and Robert A. Harrington, MD, on behalf of the CHAMPION PHOENIX Investigators

2 Disclosures Dr. Bhatt Advisory Board: Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Other: Senior Associate Editor, Journal of Invasive Cardiology; Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda. This presentation includes off-label and/or investigational uses of drugs, including clopidogrel and cangrelor. The CHAMPION PHOENIX trial was funded by The Medicines Company.

3 Antiplatelet Therapy Antiplatelet therapy is a critical part of contemporary PCI. In the era of aspirin and unfractionated heparin, intravenous glycoprotein IIb/IIIa inhibition significantly reduced important periprocedural ischemic events, but significantly increased bleeding. ADP receptor antagonism with oral agents was also shown to reduce ischemic events in PCI and especially ACS. However, available oral agents are limited by their relatively long duration of action and bioavailability, which might be a liability: if given prior to coronary angiography and urgent or emergent CABG is deemed necessary, in situations where absorption may be problematic, such as with rapid times to PCI, in patients who are intubated, nauseated, with STEMI, or shock. Harrington RA, et al. PURSUIT. NEJM 1998 Desai N and Bhatt DL. Periprocedural Antiplatelet Therapy. JACC Intervention 2010

4 Cangrelor Cangrelor is an intravenous ADP receptor antagonist that is rapidly acting, potent, and reversible, with return of normal platelet function within an hour. Cangrelor was studied previously in two large Phase 3 PCI trials, CHAMPION PCI and CHAMPION PLATFORM. Neither study met its primary endpoint, but the secondary endpoint of stent thrombosis at 48 hours was significantly reduced in CHAMPION PLATFORM and in a prespecified pooled analysis of the two trials. There was no excess in severe bleeding. The potential efficacy signal prompted us to launch the CHAMPION PHOENIX trial. Harrington RA, et al. CHAMPION PCI. NEJM 2009 Bhatt DL, et al. CHAMPION PLATFORM. NEJM 2009 White HD, et al. Meta-Analysis of CHAMPION PCI and PLATFORM. AHJ 2012

5 CHAMPION PHOENIX Executive Committee Deepak L. Bhatt, M.D., M.P.H. (Co-Principal Investigator) VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School Boston, MA Robert A. Harrington, M.D. (Co-Principal Investigator) Department of Medicine, Stanford University, Stanford, CA C. Michael Gibson, M.S., M.D. Beth Israel Deaconess Medical Center, Division of Cardiology, Boston, MA Christian W. Hamm, M.D. Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany Kenneth W. Mahaffey, M.D. Duke Clinical Research Institute, Durham, NC Matthew J. Price, M.D. Scripps Clinic and Scripps Translational Science Institute, La Jolla, CA Ph. Gabriel Steg, M.D. INSERM U-698, Université Paris-Diderot, and Hôpital Bichat, Assistance-Publique- Hôpitaux de Paris, Paris, France Gregg W. Stone, M.D. Columbia University Medical Center and the Cardiovascular Research Foundation, New York, NY Harvey D. White, D.Sc. Auckland City Hospital, Auckland, New Zealand

6 CHAMPION PHOENIX DSMB Frans Van de Werf, M.D. (Chair) Universitair Ziekenhuis Gasthuisberg, Belgium David P. Faxon, M.D. Brigham & Women s Hospital, Dept. of Medicine, Boston, MA E. Magnus Ohman, M.D. Duke University Medical Center, Durham, NC Freek W.A. Verheugt, M.D. Heartcenter University Medical Center, Amsterdam W. Douglas Weaver, M.D. Henry Ford Hospital, Detroit, MI Jan G.P. Tijssen, Ph.D. (Statistician) Department of Cardiology, Academic Medical Center-University of Amsterdam, The Netherlands

7 CHAMPION PHOENIX CEC Duke Clinical Research Institute LEADERSHIP Kenneth W. Mahaffey (Chair) Sergio Leonardi (co-chair) Dianne Gallup (Lead Statistician) Matthew D. Wilson (Project Leader) OPERATIONS Stacey Mangum (Coordinator) Linda Dowd (Lead CDA) Dimitrios Stournaras (Lead CDS) Sachin Vyas (Lead CTA) REVIEWERS Phase 1 Luciana Amaganijan Brazil Monique Anderson NC Akshay Bagai NC Robert W. Harrison NC Pedro G. Melo de Barros E Silva Brazil Phase 2 J. Matthew Brennan NC Renato D. Lopes NC Chiara Melloni NC Pierluigi Tricoci NC

8 CHAMPION PHOENIX Angiographic Core Lab Cardiovascular Research Foundation Leadership Philippe Généreux (Director) Sorin Brener Laura Lasalle Reviewers and Data Entry Staff Maria Alfonso Antoinette Allen Gerard Conditt Rosa DeJesus Champika Djurkovic Sharwat Jahan Greg Kaluza Elena Konovalova Mitchell Lustre Katharine Lymberis Duval Michel Sofia Papamitrou Nicoletta Pavlovici Khary Perry Saira Punjwani Connie Qiu Raquel Sanchez Elias Sanidas Shawnalee Vassell Douey Wright

9 CHAMPION PHOENIX A Global Trial 12 Countries 153 Sites Germany Poland Russia USA USA Italy Austria Bulgaria Czech Republic Georgia Thailand Brazil New Zealand

10 CHAMPION PHOENIX Study Design Randomized, double-blind, double-dummy, superiority Primary efficacy endpoint: Death/MI/IDR/ST at 48 hours Adjusted for 600 mg versus 300 mg clopidogrel use Modified Intent-to-Treat (MITT) analysis (patients actually got study drug and PCI) Key secondary endpoint: Stent Thrombosis at 48 hours Efficacy endpoints also examined at 30 days Primary safety endpoint: GUSTO Severe Bleeding at 48 hours MI, myocardial infarction; IDR, ischemia-driven revascularization; ST, stent thrombosis Harrington RA, et al. CHAMPION PCI. NEJM 2009 Bhatt DL, et al. CHAMPION PLATFORM. NEJM 2009 White HD, et al. Meta-Analysis of CHAMPION PCI and PLATFORM. AHJ 2012

11 CHAMPION PHOENIX Study Design CHAMPION PHOENIX N = 10,900 MITT SA/ NSTE-ACS/ STEMI Patients requiring PCI 1 P2Y 12 inhibitor naïve Rand OR Placebo 3 oral (right before PCI or right after, per physician) Cangrelor 2 bolus & infusion (30ug/kg; 4ug/kg/min) PCI ~30 Placebo 2 bolus & infusion OR Clopidogrel 600 mg oral Placebo oral Clopidogrel 3 (600 mg or 300 mg oral, per physician) to 4 hours 1 Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis. Double blind study medication was administered as soon as possible following randomization. 2 Study drug Infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of the treating physician. At the end of the infusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy. 3 Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time of patient randomization, a clopidogrel loading dose of 600 mg or 300 mg was specified by the investigator. MITT=modified intent-to-treat; NSTE-ACS=non-ST-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI.

12 Demographics, MITT Cangrelor Clopidogrel (N= 5472) (N= 5470) Age, years Female 28% 27% Diabetes mellitus 28% 28% Patient Type Stable angina 57% 55% NSTE-ACS 25% 26% STEMI 18% 19% Loading Dose 300 mg clopidogrel 26% 26% 600 mg clopidogrel 74% 74% Region United States 37% 37% Other countries 63% 63%

13 Primary Efficacy Outcomes at 48 Hours, MITT Cangrelor (N=5472) Clopidogrel (N=5470) OR (95% CI) P-value Primary Analysis Adjusted 1 Death/MI/IDR/ST 257/5470 (4.7%) 322/5469 (5.9%) 0.78 (0.66, 0.93) Secondary Efficacy Outcomes at 48 Hours, MITT Stent thrombosis (key secondary endpoint) 46/5470 (0.8%) 74/5469 (1.4%) 0.62 (0.43,0.90) 1. The logistic model was adjusted for baseline status and clopidogrel dose. P value of shown on the KM curve is log rank p value MI 207/5470 (3.8) 255/5469 (4.7) 0.80 (0.67,0.97) 0.02 Q-wave MI 11/5470 (0.2) 18/5469 (0.3) 0.61 (0.29,1.29) 0.19 IDR 28/5470 (0.5) 38/5469 ( 0.7) 0.74 (0.45,1.20) 0.22 Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99 CV Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99 Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

14 Death/ MI/ IDR/ Stent Thrombosis within 48 Hours Event Rate (%) clopidogrel 5.9% cangrelor 4.7% Log Rank P Value = Hours from Randomization Patient at Risk Cangrelor: Clopidogrel: Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

15 Stent Thrombosis within 48 Hours 2.0 Event Rate (%) clopidogrel 1.4% 0.8% cangrelor Log Rank P Value = Hours from Randomization Patient at Risk Cangrelor: Clopidogrel: Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

16 Efficacy Outcomes at 30 Days, MITT Cangrelor (N=5472) Clopidogrel (N=5470) OR (95% CI) P Value Death/MI/IDR/ST (primary endpoint, adjusted) 326/5462 (6.0%) 380/5457 (7.0%) 0.85 (0.73,0.99) 0.03 Stent thrombosis MI IDR Q-wave MI Death CV Death 71/5462 (1.3%) 225/5462 (4.1%) 14/5462 (0.3%) 56/5462 (1.0%) 60/5462 (1.1%) 48/5462 (0.9%) 104/5457 (1.9%) 272/5457 (5.0%) 22/5457 (0.4%) 66/5457 (1.2%) 55/5457 (1.0%) 46/5457 (0.8%) 0.68 (0.50,0.92) (0.68,0.98) (0.32,1.24) (0.59,1.21) (0.76,1.58) (0.69,1.57) 0.84 Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

17 Subgroups: Death/MI/IDR/ST at 48 Hours OR [95% CI] Overall 0.79 (0.67,0.93) Age (0.50,1.02) Age < (0.67,0.98) Male 0.84 (0.69,1.03) Female 0.67 (0.50,0.92) Ethnicity: White 0.80 (0.67,0.95) Ethnicity: Non-white 0.70 (0.35,1.41) United States 0.70 (0.53,0.92) Other Countries 0.85 (0.69,1.05) Stable Angina 0.78 (0.63,0.95) NSTE-ACS 0.80 (0.55,1.17) STEMI 0.75 (0.46,1.25) Weight >= (0.66,0.94) Weight < (0.39,1.45) Biomarker Positive 0.90 (0.64,1.27) Biomarker Negative 0.75 (0.61,0.91) Diabetic No 0.74 (0.61,0.90) Diabetic Yes 0.92 (0.67,1.27) Insulin-Dependent Diabetes: Yes 0.74 (0.42,1.31) Insulin-Dependent Diabetes: No 0.79 (0.66,0.94) Prior MI 0.68 (0.47,0.97) No Prior MI 0.84 (0.69,1.02) 0.2 Cangrelor Better 1.0 Clopidogrel Better 5.0 P [Int]

18 Subgroups: Death/MI/IDR/ST at 48 Hours (continued) OR [95% CI] Prior TIA/Stroke 0.78 (0.37,1.63) No Prior TIA/Stroke 0.79 (0.66,0.94) History of PAD 0.36 (0.21,0.63) No History of PAD 0.86 (0.72,1.03) History of CHF 0.73 (0.45,1.20) No History of CHF 0.80 (0.67,0.96) Clopidogrel 300 mg 0.84 (0.62,1.14) Clopidogrel 600 mg 0.77 (0.63,0.94) Bivalirudin only 0.69 (0.47,1.01) Heparin only 0.80 (0.65,0.98) Femoral 0.79 (0.65,0.96) Radial 0.76 (0.54,1.06) # vessels = (0.66,0.97) # vessels (0.49,0.99) Drug-Eluting Stent 0.80 (0.64,1.01) Bare-Metal Stent 0.77 (0.60,0.99) Aspirin 100 mg 0.80 (0.63,1.00) Aspirin >100 mg 0.70 (0.52,0.94) Clopidogrel Load before PCI Start 0.80 (0.64,0.98) Clopidogrel Load after PCI Start 0.79 (0.59,1.06) Cangrelor infusion 129 minutes 0.85 (0.68,1.07) Cangrelor infusion > 129 minutes 0.72 (0.56,0.92) 0.2 Cangrelor Better 1.0 Clopidogrel Better 5.0 P [Int]

19 Non-CABG Bleeding at 48 Hours, Safety Bleeding Scale Cangrelor (N=5529) Clopidogrel (N=5527) OR (95% CI) P Value GUSTO Severe 9 (0.16%) 6 (0.11%) 1.50 (0.53,4.22) 0.44 GUSTO Moderate 22 (0.4%) 13 (0.2%) 1.69 (0.85,3.37) 0.13 GUSTO Severe + Moderate 31 (0.6%) 19 (0.3%) 1.63 (0.92,2.90) 0.09 TIMI Major 5 (0.1%) 5 (0.1%) 1.00 (0.29,3.45) >0.999 TIMI Minor 9 (0.2%) 3 (0.1%) 3.00 (0.81,11.10) 0.08 TIMI Major + Minor 14 (0.3%) 8 (0.1%) 1.75 (0.73,4.18) 0.2 Any Blood Transfusion 25 (0.5%) 16 (0.3%) 1.56 (0.83,2.93) 0.16 ACUITY Major 235 (4.3%) 139 (2.5%) 1.72 (1.39,2.13) <0.001 ACUITY w/out hematoma 42 (0.8%) 26 (0.5%) 1.62 (0.99,2.64) 0.05 Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

20 Subgroups: GUSTO Severe/Moderate Bleeding, Safety OR [95% CI] Overall 1.63 (0.92,2.90) Age (0.45,2.53) Age < (1.02,4.93) Male 0.93 (0.41,2.12) Female 2.75 (1.16,6.51) Ethnicity: White 1.86 (0.97,3.56) Ethnicity: Non-white 1.02 (0.29,3.56) United States 1.34 (0.56,3.18) Other Countries 1.90 (0.88,4.10) Stable Angina 1.45 (0.59,3.56) NSTE-ACS 1.79 (0.52,6.13) STEMI 1.84 (0.72,4.70) Weight >= (0.80,2.86) Weight < (0.52,7.86) Biomarker Positive 1.51 (0.64,3.53) Biomarker Negative 1.76 (0.81,3.82) Diabetic No 1.90 (0.88,4.09) Diabetic Yes 1.35 (0.57,3.20) Insulin-Dependent Diabetes: Yes 3.56 (0.40,32.00) Insulin-Dependent Diabetes: No 1.52 (0.83,2.76) Prior MI 3.25 (0.65,16.12) No Prior MI 1.44 (0.78,2.67) 0.2 Cangrelor Better Clopidogrel Better P [Int]

21 Subgroups: GUSTO Severe/Moderate Bleeding, Safety (continued) OR [95% CI] Prior TIA/Stroke 0.92 (0.13,6.55) No Prior TIA/Stroke 1.72 (0.94,3.13) History of PAD NA No History of PAD 1.55 (0.84,2.87) P [Int] History of CHF 2.13 (0.39,11.70) 0.85 No History of CHF 1.79 (0.95,3.37) Clopidogrel 300 mg 4.02 (1.13,14.27) 0.09 Clopidogrel 600 mg 1.19 (0.61,2.31) Bivalirudin only 0.86 (0.26,2.83) Heparin only 1.89 (0.91,3.93) 0.26 Femoral 1.68 (0.90,3.11) Radial 1.37 (0.31,6.11) 0.81 # vessels = (0.94,3.49) # vessels (0.34,3.68) 0.48 Drug-Eluting Stent 1.26 (0.57,2.77) Bare-Metal Stent 2.17 (0.93,5.03) 0.35 Aspirin 100 mg 1.58 (0.52,4.85) Aspirin >100 mg 1.49 (0.74,3.03) 0.93 Clopidogrel Load before PCI Start 1.24 (0.58,2.66) Clopidogrel Load after PCI Start 2.53 (0.98,6.54) 0.25 Cangrelor infusion 129 minutes 1.71(0.81,3.59) Cangrelor infusion > 129 minutes 1.52(0.62,3.73) Cangrelor Better 1.0 Clopidogrel Better 5.0

22 Summary of Treatment Emergent Adverse Events Adverse Event Cangrelor (N=5529) Clopidogrel (N=5527) P Value Patients with at least one AE 20.2% 19.1% 0.13 Patients with at least one AE causing study drug discontinuation 0.5% 0.4% 0.21 Transient dyspnea 1.2% 0.3% <0.001 Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

23 Limitations A loading dose of 600 mg has become more common than 300 mg However, in the three quarters of patients who received 600 mg, the benefit of cangrelor remained statistically significant and was not attenuated. It is possible the benefits we saw here would have been attenuated with a longer duration of pretreatment. Of note, the clopidogrel pretreatment was given on the table as is consistent with many practices around the world and in particular in the United States. Importantly, prospective randomized clinical trials, namely CREDO and PRAGUE-8, did not find a significant benefit for clopidogrel pretreatment. The benefits seen here may also have been attenuated had prasugrel or ticagrelor been used in the control arm. However, to date, the largest trial of prasugrel pretreatment, ACCOAST, was terminated by the DSMB for lack of efficacy and excess bleeding. Thus, oral pretreatment, while biologically appealing and intuitive, remains unproven in prospective randomized clinical trials.

24 Conclusions In CHAMPION PHOENIX, intravenous ADP receptor antagonism with cangrelor significantly (p=0.005) reduced the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours, with a 22% odds reduction. The key secondary endpoint of stent thrombosis was also significantly reduced, with a 38% odds reduction. The benefit was sustained through 30 days. There was no excess in severe bleeding or transfusions. Intravenous cangrelor may be an attractive option across the full spectrum of PCI, including stable angina, NSTEMI, and STEMI.

25 For Full Details, Please Go to Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

26 THANK YOU!

27 BACKUP SLIDES

28 Cangrelor Direct platelet P2Y 12 receptor antagonist ATP analogue MW=800 Daltons Parenteral administration T1/2 = 3 to 6 minutes Offset = 60 minutes H N S 4Na + N N O O O P Cl Cl O P O O O P O O H O O N O H N S C F 3 Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.

29 CHAMPION PCI PLATFORM PCI all comers PCI 58% ACS on clopidogrel allowed clopidogrel 600mg administered at the start of PCI in the control arm PLATFORM all comers PCI 65% ACS clopidogrel naïve clopidogrel 600mg administered at the end of PCI in the control arm CHAMPION PCI N = 9000 SA/UA/ACS/STEMI On clopidogrel allowed Cangrelor 30µg/kg then 4µg/kg/min Clopidogrel 600 mg oral CHAMPION PLATFORM N = 6400 SA/UA/ACS No clopidogrel allowed Cangrelor 30µg/kg then 4µg/kg/min Clopidogrel 600 mg oral PCI ~25 Harrington RA, et al. NEJM 2009 Bhatt DL, et al. NEJM hours

30 Summary of Clinical Efficacy 48-Hour Events PLATFORM OR [95% CI] P value Death/MI/IDR 0.87 (0.71,1.07) 0.17 Death/Q-MI/IDR 0.55 (0.33,0.93) 0.02 Death/Q-MI/ST 0.38 (0.20,0.72) PCI Death/MI/IDR 1.05 (0.89,1.24) 0.57 Death/Q-MI/IDR 0.66 (0.42,1.05) 0.08 Death/Q-MI/ST 0.74 (0.43,1.27) 0.27 POOLED Death/MI/IDR 0.97 (0.86,1.11) 0.68 Death/Q-MI/IDR 0.61 (0.43,0.86) Death/Q-MI/ST 0.55 (0.36,0.83) Cangrelor Better Comparator Better 1. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361: Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361: White HD, Chew DP, Dauerman HL, et al. AHJ 2012.

31 CHAMPION PHOENIX Lessons from CHAMPION PCI PLATFORM Trial Design Patient population All comers PCI P2Y 12 inhibitor naïve Endpoint definitions Implementation Inclusion of patients with normal cardiac markers at baseline est. 65% trial population Patients not pre-treated with P2Y 12 inhibitor within 7 days prior to angiogram MI definition 1 Stent thrombosis definition 2 UDMI Central lab to assure consistency of CKMB mass assay globally angiographic core lab to consistently assess evidence of ischemia ARC Definition includes occurrence associated with IDR Death MI also intra-procedural stent thrombosis measured by angiographic core lab 3 1. Thygesen K, Alpert JS, and White HD, on behalf of the Joint ESC/ACCF/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J. 2007;28: Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: Brener SJ, Cristea E, Kirtane AJ, et al. Intra-Procedural Stent Thrombosis. J Am Coll Cardiol Intv 2013;6:36 43.

32 Universal Definition of MI Better discrimination of MI with consideration of multiple criteria CKMB elevations ischemic symptoms angiographic evidence ECG changes Diagnosis of MI from various perspectives Type 1 spontaneous MI related to ischemia Type 2 MI secondary to ischemia change in O 2 demand/supply Type 3 sudden unexpected cardiac death Type 4 associated with coronary angioplasty stents Type 4a MI associated with PCI Type 4b MI associated with Stent Thrombosis Type 5 MI associated with CABG Thygesen K, Alpert JS, and White HD, on behalf of the Joint ESC/ACCF/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J. 2007;28:

33 Definition of ST Angiographic Evidence: ARC ST (Academic Research Consortium) 1 Acute (<24 hours post-procedure) Subacute stent thrombosis (>24 hours and 30 days) Definite from probable stent thrombosis Adjudicated by the CEC IPST (Intra-procedural stent thrombosis) New or worsening thrombus related to the stent or Abrupt closure due to thrombosis 1. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115(17):

34 Sample Size Estimation Event rate of 5.1% in the clopidogrel arm and 3.9% in the cangrelor arm (24.5% reduction in odds ratio) N = 10,900 (power of 85% to detect this difference at the one sided significance level of 0.025) Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

35 MDCO Clinical + Data Operations LEADERSHIP Jenna Bisch (Project Lead) Tracy Survill (Data Lead) Tiepu Liu (Statistician) Steve Elkin (Programming) Markus Dietrich (Medical) PROJECT MANAGEMENT Denise Evans Tara Richardson Nita Whyte IN-HOUSE OPERATIONS Daniel Boisvert Kathie Volcy Lauren Ensley Marilu Montalvo SITE MANAGEMENT COLs Peter Djuric Cynthia Shade Mohammad Arif Linda Tilberg Katey Fox CRAs Christina Gerhardt Scott Stephens Leti Villafranca Karey Cropper Linda Willits Val Morrow DATA MANAGEMENT Cindy Clegg Kalpana Pullakhandam Michelle Arthur Gretchen Clegg Pam Hoffman Kathleen Tencer Julia Baugh Sowers Lucy Wangunyu Linda Connolly Cindy Lazos

36 CHAMPION PHOENIX AROs and CROs Partners Almac Merge Quest Bioclinica Cardiovascular Research Foundation Duke Clinical Research Institute Green Lane Coordinating Center Worldwide Clinical Trials MDCO Role IVRS/IWRS ecrf CKMB central lab Web portal for angiographic film uploads Angiographic Core Lab CEC Site Management New Zealand Site Management ROW excl. US + NZ Site Management - US

37 Patient Disposition Enrolled patients with Stable Angina/NSTE-ACS/STEMI Indicated for PCI (N=11,145) 1:1 Randomization No PCI (N=91) Did Not Receive Study Drug (N=52) No PCI / No Study Drug (N=109) ITT CANGRELOR (N=5581) MITT CANGRELOR (N=5472) ITT CLOPIDOGREL (N=5564) MITT CLOPIDOGREL (N=5470) No PCI (N=83) Did Not Receive Study Drug (N=37) No PCI / No Study Drug (N=94) Lost to follow-up (N=2) PCI PCI Withdrew Consent (N=1) Lost to follow-up (N=8) 48 hour follow-up (N=5470) 30 day follow-up (N=5462) 48 hour follow-up (N=5469) 30 day follow-up (N=5457) Lost to follow-up (N=9)

38 Primary Efficacy Outcome at 48 Hours, MITT Cangrelor (N=5472) Clopidogrel (N=5470) OR (95% CI) P-value Primary Analysis Adjusted 1 Death/MI/IDR/ST 257/5470 (4.7%) 322/5469 (5.9%) 0.78 (0.66, 0.93) Clopidogrel Loading 300 mg 81/ 1405 (5.8%) 95/ 1401 (6.8%) 0.84 (0.62,1.14) mg 176/ 4065 (4.3%) 227/ 4068 (5.6%) 0.77 (0.63,0.94) The logistic model was adjusted for baseline status and clopidogrel dose. MI, myocardial infarction; IDR, ischemia-driven revascularization; ST, stent thrombosis Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

39 Efficacy Outcomes at 48 Hours, ITT Cangrelor (N=5581) Clopidogrel (N=5564) OR (95% CI) P Value Death/MI/IDR/ST (primary endpoint, adjusted) 260/5573 (4.7%) 325/5561 (5.8%) 0.79 (0.67,0.93) Stent thrombosis (key secondary endpoint) 46/5573 (0.8%) 74/5561 (1.3%) 0.62 (0.43,0.89) 0.01 MI 207/5573 (3.7) 255/5561 (4.6) 0.80 (0.67,0.97) 0.02 Q-wave MI 11/5573 (0.2) 18/5561 (0.3) 0.61 (0.29,1.29) 0.19 IDR 29/5573 (0.5) 38/5561 ( 0.7) 0.76 (0.47,1.23) 0.27 Death 20/5573 (0.4) 21/5561 (0.4) 0.95 (0.51,1.75) 0.87 CV Death 20/5573 (0.4) 21/5561 (0.4) 0.95 (0.51,1.75) 0.87 MI, myocardial infarction; IDR, ischemia-driven revascularization; ST, stent thrombosis Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at